tbuckley/cabot-search huggingface dataset:
Predictors of 5-Year Mortality in Patients Managed With a Magnetically Levitated Left Ventricular Assist Device
Authors: Aditi Nayak, Shelley A. Hall, Nir Uriel, Daniel J. Goldstein, Joseph C. Cleveland, Jennifer A. Cowger, Christopher T. Salerno, Yoshifumi Naka, Douglas Horstmanshof, Daniel Crandall, AiJia Wang, Mandeep R. Mehra
Journal: Journal of the American College of Cardiology (2023)

In advanced heart failure patients implanted with a fully magnetically levitated HeartMate 3 (HM3, Abbott) left ventricular assist device (LVAD), it is unknown how preimplant factors and postimplant index hospitalization events influence 5-year mortality in those able to be discharged. The goal was to identify risk predictors of mortality through 5 years among HM3 LVAD recipients conditional on discharge from index hospitalization in the MOMENTUM 3 pivotal trial. This analysis evaluated 485 of 515 (94%) patients discharged after implantation of the HM3 LVAD. Preimplant (baseline), implant surgery, and index hospitalization characteristics were analyzed individually, and as multivariable predictors for mortality risk through 5 years. Cumulative 5-year mortality in the cohort (median age: 62 years, 80% male, 65% White, 61% destination therapy due to transplant ineligibility) was 38%. Two preimplant characteristics (elevated blood urea nitrogen and prior coronary artery bypass graft or valve procedure) and 3 postimplant characteristics (hemocompatibility-related adverse events, ventricular arrhythmias, and estimated glomerular filtration rate <60 mL/min/1.73 m2 at discharge) were predictors of 5-year mortality. In 171 of 485 patients (35.3%) without any risk predictors, 5-year mortality was reduced to 22.6% (95% CI: 15.4%-32.7%). Even among those with 1 or more predictors, mortality was <50% at 5 years (45.7% [95% CI: 39.0%-52.8%]). Long-term survival in successfully discharged HM3 LVAD recipients is largely influenced by clinical events experienced during the index surgical hospitalization in tandem with baseline factors, with mortality of <50% at 5 years. In patients without identified predictors of risk, long-term 5-year mortality is low and rivals that achieved with heart transplantation, even though most were implanted with destination therapy intent. (MOMENTUM 3 IDE Clinical Study Protocol, NCT02224755; MOMENTUM 3 Pivotal Cohort Extended Follow-up PAS, NCT03982979)
Prevalence, Characteristics, and Prognostic Relevance of Donor-Transmitted Coronary Artery Disease in Heart Transplant Recipients
Authors: David Couto-Mallón, Luis Almenar-Bonet, Eduardo Barge-Caballero, Francisco José Hernández-Pérez, Juan Carlos López-Azor García, María Jesús Valero-Masa, María Ángeles Castel-Lavilla, Sonia Mirabet-Pérez, Iris Paula Garrido-Bravo, Carles Díez-López, Amador López-Granados, Rebeca Manrique-Antón, Carmen Neri Fernández-Pombo, Javier Muñiz, Maria Generosa Crespo-Leiro
Journal: Journal of the American College of Cardiology (2023)
Sex Differences in Thoracic Aortic Disease and Dissection
Authors: Daniela Crousillat, Joan Briller, Niti Aggarwal, Leslie Cho, Thais Coutinho, Colleen Harrington, Eric Isselbacher, Kathryn Lindley, Maral Ouzounian, Ourania Preventza, Jyoti Sharma, Ranya Sweis, Melissa Russo, Nandita Scott, Nupoor Narula
Journal: Journal of the American College of Cardiology (2023)
The Molecular Therapy family of journals continues to lead the field of gene and cell therapy
Authors: Courtney Bricker-Anthony, Roland W. Herzog
Journal: Molecular Therapy (2023)

The past 2 years have witnessed many changes and challenges at the Molecular Therapy family of journals: a new Editor-in-Chief and section editors at Molecular Therapy – Nucleic Acids, the introduction of a fully staffed editorial office to help handle the sustained growth of all four journals, and the implementation of new procedures to prevent the infiltration of papermill papers, to name a few. Our attitudes toward the impact factor (IF) have also changed significantly. 1 Bricker-Anthony C. Herzog R.W. Distortion of journal impact factors in the era of paper mills. Mol. Ther. 2023; 31: 1503-1504https://doi.org/10.1016/j.ymthe.2023.05.008 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar No single metric can define success, and we believe that our journals are proof of that.
P578: EFFECTIVENESS OF REINDUCTION CHEMOTHERAPY USING BORTEZOMIB WITH HOMOHARRINGTONINE AND CYTARABINE IN REFRACTORY OR RELAPSED ACUTE MYELOID LEUKEMIA: A PHASE II, MULTICENTER, PROSPECTIVE CLINICAL TRIAL
Authors: Chengtao Zhang, Da Gao, Xiaohong Wang, Xiuli Sun, Yan Yan, Jingjing Zhang, Yan Yang, Jinsong Yan
Journal: HemaSphere (2023)

Background: Refractory/relapsed acute myeloid leukemia (R/R AML) has unsatisfactory outcomes even after allogeneic hematopoietic stem cell transplantation. Long-term survival is mainly influenced by complete remission (CR) rates after reinduction therapie Aims: To investigate the CR/CR with incomplete hematologic recovery (CRi) rates and adverse events in a new R/R AML reinduction therapy (bortezomib, homoharringtonine, and cytarabine [BHA]) Methods: We enrolled 21 patients with R/R AML (median age, 42 [range, 30–62] years), who received BHA reinduction therapy (bortezomib, 1.3 mg/m2/day on days 1 and 4; homoharringtonine, 4 mg/m2/day and cytarabine, 1.5 g/m2/day for 5 days). CR and adverse events were assessed Results: After one BHA course, the CR/CRi and partial remission rates were 38.1% and 14.3%, respectively (overall response rate, 52.4%). Among 21 patients, 9 harbored FLT3-ITD or FLT3-TKD mutations. Overall response and CR/CRi rates in FLT3-mutated R/R-AML reached 66.7% (P=0.03 vs that in FLT3 wild-type R/R AML). After reinduction therapy, allogeneic hematopoietic stem cell transplantation or consolidation chemotherapy led to a one-year overall survival rate of 27.8% in all patients. The one-year relapse-free survival rate was 50% in 8 patients who had achieved CR/CRi after one BHA course. During reinduction, common non-hematologic adverse grade 3/4 events were infection (90.5%), hypokalemia (14.4%), hypocalcemia (14.3%), and mucositis (9.5%). In patients achieving CR, the median time to neutrophil count >0.5×109/L and time to platelet count >20×109/L were 15 (13–17) days and 13 (13–18) days, respectively. Overall, this novel regimen was well tolerated, with a 30-day mortality of 4.8%. Conclusion: BHA chemotherapy was safe and can serve as a reinduction therapy for R/R AML, particularly with FLT3 mutation. The higher response rate will pave a way for potential long-term survival in patients with R/R-AML, especially for those with FLT3 mutation. Clinical Trial registration:https://www.chictr.org.cn/, identifier [ChiCTR2000029841]. Keywords: acute myeloid leukemia, refractory and relapsed, bortezomib, homoharringtonine, FLT3 mutation, reinduction Figure 1 Overall SurvivalFigure 1. The 1-year estimated overall survival in all patients.The 1-year estimated overall survival was 27.8% in all patients. Keywords: Allogeneic hematopoietic stem cell transplant, relapsed/refractory, Acute myeloid leukemia, FLT3
Neighborhood Childhood Opportunity, Race/Ethnicity, and Surgical Outcomes in Children With Congenital Heart Disease
Authors: Son Q. Duong, Mahmud O. Elfituri, Isabella Zaniletti, Robert W. Ressler, Clemens Noelke, Bruce D. Gelb, Robert H. Pass, Carol R. Horowitz, Howard S. Seiden, Brett R. Anderson
Journal: Journal of the American College of Cardiology (2023)
LIGHTing CAR T in the tumor microenvironment
Authors: Yong Liang, Yang-Xin Fu
Journal: Molecular Therapy (2023)

Adoptive cell therapy using T cells expressing chimeric antigen receptors (CAR T) has demonstrated remarkable efficacy in hematological malignancies. However, CAR T therapy has shown limited responses in solid tumors, which may be due to inefficient CAR T cell recruitment, activation, and survival inside the suppressive tumor microenvironment (TME). The expression of the tumor necrosis factor superfamily member 14 (TNFSF14 or LIGHT) inside the TME promotes the expression of chemokines to form tertiary lymphoid structures (TLSs), which improves the recruitment and expansion of T cells as well as resistance to the suppressive TME. 1 Yu P. Lee Y. Liu W. Chin R.K. Wang J. Wang Y. Schietinger A. Philip M. Schreiber H. Fu Y.X. Priming of naive T cells inside tumors leads to eradication of established tumors. Nat. Immunol. 2004; 5: 141-149 Crossref PubMed Scopus (305) Google Scholar In this issue, Zhang et al. engineered LIGHT-expressing CAR T cells, resulting in the accumulation of the LIGHT-CAR T cells and potent tumor killing activities in both syngeneic and xenograft mouse models. 2 Zhang N. Liu X.H. Qin J.L. Sun Y. Xiong H. Lin B.X. Liu K.X. Tan B.H. Zhang C.L. Huang C.S. et al. LIGHT/TNFSF promotes CAR-T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment.. Mol. Ther. 2023; 31: 2575-2590 Abstract Full Text Full Text PDF Scopus (2) Google Scholar LIGHT/TNFSF14 promotes CAR-T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironmentZhang et al.Molecular TherapyJuly 4, 2023In BriefDu and colleagues established novel LIGHT/TNFSF14-secreting CAR-T cells that have significantly enhanced trafficking, cytotoxicity, and clinical potential to solid tumors through reconstituting normalized tumor vasculature and tertiary lymphoid structures (TLSs) in the tumor microenvironment. Full-Text PDF
S309: SUSTAINED INHIBITION OF PLATELET ACTIVITY AND THROMBOSIS VIA IV AND ORAL ADMINISTRATION OF CS585
Authors: Sylviane Lambert, Andrew Rickenberg, Bjorn Dahlof, Niklas Bergh, Michael Holinstat
Journal: HemaSphere (2023)

Background: Uncontrolled platelet activation leads to the formation of occlusive thrombi resulting in myocardial infarction, stroke, VTE, and critical limb ischemia. There remains an unmet need for more efficacious anti-thrombotics that have sustainability in the blood. Our group recently identified a novel oxidized lipid in the blood that not only inhibits platelet function and thrombosis through activation of the prostacyclin (IP) receptor, but is both IV and orally available and exhibits a sustained inhibition of clot formation and thrombosis in vivo. Aims: Develop an antiplatelet drug, CS585, that is available by IV or oral administration and elicits an effective and sustained inhibition of platelet function and thrombosis in vivo. Methods: Using mouse thrombosis models, we assessed the ability of CS585 to induce a sustained inhibition of platelet activation and thrombosis following a one-time IV or oral administration. Thrombosis was assessed in real-time using antibody-labelled platelet and fibrin at multiple times following administration. Platelet accumulation and thrombosis were assessed using in vivo intravital confocal microscopy. Results:In vivo inhibition of injury-induced thrombosis in the cremaster arterioles by CS585 was demonstrated by measuring fibrin and platelet clot formation, stability, and accumulation at the site vessel injury. Imaging was conducted at various time points following CS585 administered either IV or by oral gavage. CS585 was observed to inhibit platelet accumulation but not fibrin formation through both routes of administration. Inhibition of clot formation was observed by IV administration as well as by oral gavage for the 18 hours tested in this study. Further, inhibition by oral gavage showed inhibition of platelet clot formation at the site of injury, dose-dependent, with as little as 1 mg/kg dosing of CS585. Summary/Conclusion: We have shown for the first time that CS585, a novel compound targeting and activating the IP receptor, inhibits in vivo platelet activation and thrombosis for at least 18 hours post administration. CS585 was shown to exhibit this prolonged inhibition of thrombosis when administered either through IV or by oral gavage. This discovery supports CS585 as a viable and new approach for prolonged prevention of platelet activation and thrombosis and potential protection from myocardial infarction, stroke, VTE, and critical limb ischemia.Figure: CS585 dose-dependently inhibits laser-induced thrombosis. Platelet accumulation (green) and fibrin formation (red). CS585 dosed in animals orally 0.5-6 mg/kg prior to injury. Keywords: Arterial thrombosis, Anti-platelet therapies, Antithrombotic therapy
S240: TARGETING PRMT1 ALLEVIATES CHRONIC GRAFT-VERSUS-HOST DISEASE BY REDUCING T AND B PATHOGENICITY
Authors: Xiaoyan Zhao, LI Cai, Huafang Wang
Journal: HemaSphere (2023)

Topic: 21. Stem cell transplantation - Experimental Background: Chronic graft-versus-host disease (cGVHD) is a common complication after allogeneic hematopoietic stem cell transplantation, which is characterized by the production of autoantibodies and autoimmune-like fibrosis mediated by pathogenic T and B cells. Recent studies have reported that Protein arginine methyltransferase 1 (PRMT1)-catalyzed arginine methylation is essential for the differentiation and proliferation of T cells and B cells, suggesting that PRMT1 may play an important role in the regulation of cGVHD. Aims: We aimed to investigate the mechanism by which PRMT1 regulates T and B cell pathogenicity in cGVHD, and to determine whether inhibiting PRTM1 alleviates cGVHD. Methods: 60 peripheral blood samples from patients with cGVHD and 25 peripheral blood samples from patients without cGVHD underwent allo-HSCT were collected. The scleroderma-like cGVHD and lupus-like cGVHD mice models were established. The expression of PRMT1 in CD4+T cells and B cells was evaluated by western blotting and Real-time Polymerase Chain Reaction (RT-PCR). The activation, proliferation and differentiation of CD4+T and B cells from cGVHD mice and the samples of cGVHD patients after the treatment of the selective PRMT1 inhibitor, TCE5003, were measured using flow cytometry. The molecular mechanism of PRMT1 regulating T and B cells pathogenicity was investigated using western blotting and RT-PCR. Results: In this study, we confirmed that PRMT1 was involved in the pathogenesis of cGVHD. We observed that PRMT1 expressions were upregulated in CD4+T cells and B cells in patients with cGVHD and in mice with scleroderma-like and lupus-like cGVHD. However, inhibiting PRMT1 with the selective PRMT1 inhibitor, TCE5003, significantly alleviated scleroderma-like and lupus-like cGVHD in mice by reducing Th17 cells differentiation and germinal center B cells response. Moreover, it was consistently revealed that inhibiting PRMT1 weakened the differentiation of Th17 cells, B cells proliferation and antibody secretion functions in human cGVHD patients. In addition, further studies revealed that PRMT1 regulated B cells proliferation and antibody secretion functions through methylating I isocitrate dehydrogenase 2 (IDH2). Importantly, we observed that asymmetric di-methylation of IDH2 by PRMT1 at arginine 353 site promoted the formation of IDH2 homodimer, which in turn enhanced IDH2 enzyme activity, further enhancing proliferation and antibody secretion functions of B cell in cGVHD patients. Summary/Conclusion: In summary, the current work reveals a critical role for PRMT1 in cGVHD pathogenesis and provides a rationale for the application of PRMT1 inhibitor in cGVHD treatment. Keywords: B cell, Chronic graft-versus-host, T cell, Bone marrow transplant
P338: SLC7A11 PROMOTES ARGININE BIOSYNTHESIS IN ACUTE LYMPHOBLASTIC LEUKEMIA WITH IMMUNOTHERAPEUTIC POTENTIAL
Authors: Jiazheng LI, Yanxin Chen, Yongzhi Zheng, Jianda Hu
Journal: HemaSphere (2023)

Background: Most acute lymphoblastic leukemia (ALL) patients are treated with chemotherapy as primary care. Although treatment response is usually positive, resistance and relapse often occur through unclear mechanisms. Solute Carrier Family 7 Member 11 (SLC7A11) is a key molecule involved in ferroptosis, and the characteristics of SLC7A11 in ALL are still uncertain.. Aims: This study aimed to explore the effect of SLC7A11 on drug resistance and prognosis, and the therapeutic potential against ALL. Methods: Transcription profile of 68 ALL patients, ALL Nalm6 parental and resistant (Nalm6/ADR) cell line were performed to identify candidate ALL resistance genes. The biological function of SLC7A11 on integrated RNA-seq and metabolomic analysis, cell growth, lipid peroxidation, and drug sensitivity were used to explore in ALL cell line Jurkat and Nalm6. The ESTIMATE score was utilized to assess the gene expression correlation with immune microenvironment by the TARGET ALL P2 database. Results: Differential expression genes (DEGs) were screened from both groups, the minimal residual disease (MRD)High (>1%) group in comparison with MRDlow (<0.01%), Nalm6 and Nalm6/ADR, respectively. Further common DEGs (co‐DEGs) analyses were carried out and gene expression was validated in Nalm6 and Nalm6/ADR. Then, SLC7A11, which had the highest log 2 |fold change| value (3.466) in the clinical group, was identified as a candidate resistance gene in ALL. Overexpression of SLC7A11 in Jurkat and Nalm6 cells promoted cell proliferation, cellular lipid peroxidation, and decreased the drug sensitivity of Venetoclax (P=0.033) and Adriamycin (P=0.002) via decreasing arginine biosynthesis, while knockdown of SLC7A11 had the opposite effect. Notably, Tumor Necrosis Factor Superfamily Member 13b (TNFSF13B), a cytokine, had a positive correlation with ESTIMATE score, while the expression of SLC7A11 had a negative correlation by TARGET P2 ALL database. What’s more, SLC7A11 and TNFSF13B was observed negative correlation in our 68 ALL patients. Summary/Conclusion: SLC7A11 promotes cell proliferation and mediates resistance though reprogramming arginine biosynthesis of ALL. What more, SLC7A11-mediated modulation of TNFSF13B may be evidence to overcome resistance in ALL, while targeting the metabolism and immune microenvironment. Keywords: BAFF, ALL, Arginine
P391: PROGNOSTIC ANALYSIS OF RELAPSED PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA TREATED BY CCLG-ALL2008 PROTOCOL IN CHINA
Authors: Ning Wang, Xiao-Juan Chen, Xiao-Fan Zhu
Journal: HemaSphere (2023)

Background: Even though the survival rate of pediatric acute lymphoblastic leukemia (ALL) is gradually improving in recent years, about 20% of patients suffer from relapse, resulting in treatment failure and the leading cause of death. Aims: To investigate the clinical features of relapsed pediatric ALL for clues of therapeutic regimen optimization. Methods: The data of 939 childhood ALL diagnosed and managed by the CCLG-ALL 2008 protocol between April 2008 and April 2015 was collected. A retrospective analysis was performed for the clinical features of 217 relapsed children. Results: Of 939 pediatric ALL, there were 906 children (96.5%) achieved first complete remission (CR1) after induction therapy. 217 children (24%) relapsed until February 2023. The 5-year OS for relapsed children was 23.0%. Relapse sites included isolated extramedullary relapse (7%), isolated BM relapse (83%), and combined (10%) and their 5-year OS was 79.4%, 17.4%, and 28.6% respectively (p<0.05). As for time to relapse, the 5-year OS for very early stage (42%), early stage (31%) and late stage (27%) relapse was 8.4%, 15.9% and 26.7% respectively (p<0.05). Based on the UK-ALLR3 protocol, relapsed children were stratified into standard-risk (4.2%), intermediate-risk (28.1%), and high-risk groups (67.7%) and the 5-year OS was 100%, 41.0%, and 10.6% respectively (p<0.05). After relapse, 134 children (61.8%) accepted reinduction therapy. The secondary CR (CR2) rate and 5-year OS after CR2 was 64.9% and 53.5% respectively. Among 81 high-risk children accepted reinduction (55.1%), 5-year OS was 46.3% for those accepted hematopoietic stem cell transplantation (HSCT) and 6.1% without HSCT (p<0.05). Summary/Conclusion: Relapses mainly occurred at the very early stage and isolated BM, which also predict a poor survival rate. Central nervous system (CNS) involvement at diagnosis and immunophenotype have no significant impact on the median survival time among relapsed children. HSCT after relapse could rescue the survival rate of high-risk children, which needs further verification with the development of new strategies such as cellular immunotherapy.Keywords: Relapse, Pediatric, ALL
S307: CEVIDOPLENIB (SKI-O-703), A NOVEL SYK INHIBITOR, REDUCES ANTIPHOSPHOLIPID ANTIBODY TITERS AND PREVENTS INTRAMYOCARDIAL SMALL ARTERIAL THROMBOSIS IN A MOUSE MODEL OF ANTIPHOSPHOLIPID SYNDROME
Authors: Eunkyeong Jang, Haejun Hwang, Taeyoung Yoon, Ji Hyeon Roh, Woo Jin Kim, Jeehee Youn
Journal: HemaSphere (2023)

Background: Antiphospholipid syndrome (APS) is an autoantibody-mediated blood disorder where the antiphospholipid antibodies (APLs) may cause blood clots to form in arteries and veins potentially leading to life-threatening conditions such as a heart attack or strokes and obstetric complications. There is no disease-modifying medication currently available other than anti-thrombotic treatments. Cevidoplenib (SKI-O-703) is a potent and selective inhibitor of spleen tyrosine kinase (SYK). It recently completed Phase II study in patients with immune thrombocytopenia (ITP; the data presented in this meeting). Aims: By inhibiting antiphospholipid antibody-induced activation of B cell receptor (BCR) and Fc receptor (FcR), it is anticipated that inhibition SYK might be an effective strategy to lower the levels of autoantibodies and the risk of blood clot formation. This study aims to test the hypothesis in a mouse model of APS. Methods: A mouse model of primary APS was established by subcutaneous injection of human beta2GP1 in BALB/c mice, where dramatic increases in the level of anti-beta2GP1 and anti-cardiolipin IgG antibodies as well as significant pan-cytopenia were observed at 12-week post-immunization, along with evident histopathologic changes in cardiac tissues such as intramyocardial small arterial thrombosis and epicardial calcification. In the therapeutic model, the mice were administered with cevidoplenib (42 and 84 mg/kg qd, po) from day 3 post-immunization for 16 weeks. Blood samples were collected at weeks 5, 9, 11, and 14 for analysis of autoantibody levels by ELISA and, at the end of treatment, cardiac tissues were examined by IHC and spleen cells by FACS. In addition, lupus anticoagulant testing was also performed. Results: Cevidoplenib treatment was effective at lowering the levels of APLs and it dramatically reduced the incidence of histological findings in cardiac tissue. Although spleen cells were not noticeably altered, prothrombin time and fibrinogen levels were significantly reduced. Summary/Conclusion: Most pathological signs of APS, especially that of cardiac histology, were significantly improved by administration of cevidoplenib in the mouse model. Specific inhibition of SYK appears to be a promising immunotherapeutic, disease-modifying approach to lowering the risk of thrombotic events in APS patients. Keywords: Antiphospholipid syndrome, SYK, Antiphospholipid antibody
Safety and efficacy of inhaled IBIO123 for mild-to-moderate COVID-19: a randomised, double-blind, dose-ascending, placebo-controlled, phase 1/2 trial
Authors: Bruno Maranda, Sébastien M Labbé, Magali Lurquin, Pascal Brabant, Alexandre Fugère, Jean-François Larrivée, Djordje Grbic, Annie Leroux, Frédéric Leduc, Andrés Finzi, Simon Gaudreau, Yolandi Swart
Journal: The Lancet Infectious Diseases (2023)
A-GCL: Adversarial graph contrastive learning for fMRI analysis to diagnose neurodevelopmental disorders
Authors: Shengjie Zhang, Xiang Chen, Xin Shen, Bohan Ren, Ziqi Yu, Haibo Yang, Xi Jiang, Dinggang Shen, Yuan Zhou, Xiao-Yong Zhang
Journal: Medical Image Analysis (2023)